                HIGHLIGHTS OF PRESCRIBING INFORMATION                                                   -------------------------WARNINGS AND PRECAUTIONS---------------------­
               These highlights do not include all the information needed to use                        •    Myelosuppression: Monitor blood counts before and during treatment with
               IWILFIN™ safely and effectively. See full prescribing information for                         IWILFIN. Withhold, reduce dose, or permanently discontinue based on
               IWILFIN.                                                                                      severity. (5.1)
               IWILFIN™ (eflornithine) tablets, for oral use                                            •    Hepatotoxicity: Monitor liver function tests before and during treatment
               Initial U.S. Approval: 2023                                                                   with IWILFIN. Withhold, reduce dose, or permanently discontinue based
                                                                                                             on severity. (5.2)
             ----------------------------INDICATIONS AND USAGE--------------------------­               •    Hearing Loss: Monitor hearing before and during treatment with IWILFIN.
             IWILFIN is an ornithine decarboxylase inhibitor indicated to reduce the risk of                 Withhold, reduce dose, or permanently discontinue based on severity. (5.3)
             relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who            •    Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
             have demonstrated at least a partial response to prior multiagent,                              reproductive potential of the potential risk to a fetus and to use effective
             multimodality therapy including anti-GD2 immunotherapy. (1)                                     contraception. (5.4, 8.1, 8.3)
                                                                                                        ----------------------------ADVERSE REACTIONS --------------------------­
             ------------------------DOSAGE AND ADMINISTRATION---------------------­                    •    Mostcommonadversereactions(incidence ≥5%)are hearing loss, otitis
             •   Prior to initiation of IWILFIN, perform baseline audiogram, complete blood count, and       media, pyrexia, pneumonia, and diarrhea. (6.1)
                 liver function tests. (2.1, 5.3)                                                       •    Most common Grade 3 or 4 laboratory abnormalities (incidence ≥2%) are increased
             •   Recommended dosage of IWILFIN is based on body surface area (see Table 1). (2.2)            ALT, increased AST, decreased neutrophil count, and decreased hemoglobin. (6.1)
             •   IWILFIN is taken orally twice daily with or without food until disease
                 progression, unacceptable toxicity, or for a maximum of two years. (2.2)               Toreport SUSPECTED ADVERSE REACTIONS, contact US WorldMeds
             •   IWILFIN tablets may be swallowed whole, chewed, or crushed and mixed with              at 1-877-IWILFIN or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
                 soft food or liquid. (2.4)
                                                                                                        -----------------------USE IN SPECIFIC POPULATIONS ----------------------­
             ---------------------DOSAGE FORMS AND STRENGTHS ---------------------­                          Lactation: Advise not to breastfeed. (8.2)
             Tablets: 192 mg (3)
                                                                                                        See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
             ----------------------------CONTRAINDICATIONS--------------------------------­             patient labeling.
             None (4)
                                                                                                                                                                                              Revised: 12/2023



               FULL PRESCRIBING INFORMATION: CONTENTS*
               1      INDICATIONS AND USAGE                                                                11    DESCRIPTION
                2     DOSAGE AND ADMINISTRATION                                                            12    CLINICAL PHARMACOLOGY
                      2.1         Recommended Testing Before Initiating IWILFIN                                  12.1        Mechanism of Action
                      2.2         Recommended Dosage of IWILFIN                                                  12.2        Pharmacodynamics
                      2.3         Dosage Modifications for Adverse Reactions                                     12.3        Pharmacokinetics
                      2.4         Administration, Crushed Preparation, and Missed Dose                     13    NONCLINICAL TOXICOLOGY
                                  Instructions                                                                   13.1        Carcinogenesis, Mutagenesis, Impairment of Fertility
                3     DOSAGE FORMS ANDSTRENGTHS                                                            14    CLINICAL STUDIES
                4     CONTRAINDICATIONS                                                                    16    HOW SUPPLIED/STORAGE AND HANDLING
                5     WARNINGS AND PRECAUTIONS                                                             17    PATIENT COUNSELING INFORMATION
                      5.1         Myelosuppression                                                      *Sections or subsections omitted from the full prescribing information are not
                      5.2         Hepatotoxicity                                                        listed.
                      5.3         Hearing Loss
                      5.4         Embryofetal Toxicity
                6     ADVERSE REACTIONS
                      6.1         Clinical Trials Experience
                8     USE IN SPECIFIC POPULATIONS
                      8.1         Pregnancy
                      8.2         Lactation
                      8.3         Females and Males of Reproductive Potential
                      8.4         Pediatric Use
















Reference ID: 5293147
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          FULL PRESCRIBING INFORMATION
          1                     INDICATIONS AND USAGE
          IWILFIN (eflornithine) is indicated to reduce the risk of relapse in adult and pediatric patients with high-risk
          neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality
          therapy including anti-GD2 immunotherapy.
          2                     DOSAGE AND ADMINISTRATION
          2.1                   Recommended Testing Before Initiating IWILFIN
          Prior to initiating IWILFIN, perform complete blood count, liver function tests, and baseline audiogram [see
          Warnings and Precautions (5.1-5.3)].
          2.2                   Recommended Dosage of IWILFIN
          The recommended IWILFIN dosage, based on body surface area (BSA), is provided in Table 1.
          Recalculate the BSA dosage every 3 months during treatment with IWILFIN.
          Table 1:                     Recommended Dose
            Body Surface Area (m2)                                Dosage
            >1.5                                                  768 mg (four tablets) orally twice a day
            0.75 to 1.5                                           576 mg (three tablets) orally twice a day
            0.5 to < 0.75                                         384 mg (two tablets) orally twice a day
            0.25 to < 0.5                                         192 mg (one tablet) orally twice a day
          2.3 Dosage Modifications for Adverse Reactions
          The recommended dose reductions for adverse reactions are provided in Table 2.
          Table 2:                      Recommended IWILFIN Dose Reductions for Toxicity Management
            Current Dose                                                                                                 Reduced Dose
            768 mg (four tablets) orally twice a day                                                                     576 mg (three tablets) orally twice a day
            576 mg (three tablets) orally twice a day                                                                    384 mg (two tablets) orally twice a day
            384 mg (two tablets) orally twice a day                                                                      192 mg (one tablet) orally twice a day
            192 mg (one tablet) orally twice a day                                                                       192 mg (one tablet) orally once daily
          If subsequent adverse reactions occur, continue dose reduction until reaching the minimum dose of one 192 mg
          tablet once per day. Permanently discontinue IWILFIN if the patient is unable to tolerate the minimum dose of
          192 mg once daily.


Reference ID: 5293147
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           The recommended dosage modifications of IWILFIN for the management of adverse reactions are provided in
           Table 3.
           Table 3:                     Recommended IWILFIN Dosage Modifications for Adverse Reactions
             Adverse Reaction                                             Severity*                                 Dosage Modification
             Myelosuppression [see Warnings and Precautions (5.1)]
             Neutrophil count decreased                                   <500/mm3                                  Withhold IWILFIN until recovery to ≥500/mm3                  .
                                                                                                                           •       If recovered within 7 days, resume IWILFIN
                                                                                                                                   at the same dose.
                                                                                                                           •       If recovered after 7 days, resume IWILFIN at
                                                                                                                                   the next reduced dose level.
             Platelet count decreased                                     <25,000/mm3                               Withhold IWILFIN until recovery to ≥25,000/mm3                  .
                                                                                                                           •       If recovered within 7 days, resume IWILFIN
                                                                                                                                   at the same dose.
                                                                                                                           •       If recovered between 7 and 14 days, resume
                                                                                                                                   IWILFIN at the next reduced dose level.
                                                                                                                    If not recovered within 14 days, permanently
                                                                                                                    discontinue IWILFIN.
             Anemia                                                       <8g/dL                                    Withhold IWILFIN until recovery to ≥8g/dL.
                                                                                                                           •       Resume IWILFIN at the same dose.
                                                                                                                    If anemia recurs (<8g/dL)
                                                                                                                           •       Withhold IWILFIN until recovery to ≥8g/dL.
                                                                                                                           •       Resume IWILFIN at the next reduced dose
                                                                                                                                   level.
             Hepatotoxicity [see Warnings and Precautions (5.2)]
             Aspartate aminotransferase                                   AST or ALT ≥10 ×                          Withhold IWILFIN until recovery to <10 × ULN.
             increased                                                    ULN                                              •       If recovered within 7 days, resume IWILFIN
             or                                                                                                                    at the same dose.
             Alanine aminotransferase                                                                                      •       If recovered after 7 days, resume IWILFIN at
             increased                                                                                                             the next reduced dose level.
             Hearing Loss [see Warnings and Precautions (5.3)]


Reference ID: 5293147
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             Adverse Reaction                                             Severity*                                      Dosage Modification
             Hearing loss                                                 Clinically concerning                          Continue dosing with IWILFIN and repeat
                                                                          new or worsening                               audiogram in 3 weeks.
                                                                          hearing loss compared                                 •       If improved, continue IWILFIN at the same
                                                                          to IWILFIN baseline                                           dose.
                                                                          audiogram                                             •       If clinically concerning changes persist, hold
                                                                                                                                        IWILFIN for up to 30 days and repeat
                                                                                                                                        audiogram.
                                                                                                                         If stable or improved, resume IWILFIN at the next
                                                                                                                         reduced dose level.
             Other Adverse Reactions [see Adverse Reactions (6.1)]
             Nausea, vomiting, or                                         Grade 3                                        If symptoms respond to supportive treatment (e.g.,
             diarrhea                                                                                                    anti-emetic, anti-diarrheal), continue dosing with
                                                                                                                         IWILFIN at the same dose.
                                                                                                                         If symptoms do not respond to treatment,
                                                                                                                                •       Withhold IWILFIN until recovery to ≤ Grade
                                                                                                                                        2.
                                                                                                                                •       Resume IWILFIN at the next reduced dose
                                                                                                                                        level.
             Other adverse reactions                                      Grade 3 or 4                                   Withhold IWILFIN until recovery to ≤ Grade 2.
                                                                                                                                •       Resume IWILFIN at the next reduced dose
                                                                                                                                        level.
                                                                          Recurrent Grade 4                              Permanently discontinue IWILFIN.
           *Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03
           2.4                  Administration, Crushed Preparation, and Missed Dose Instructions
           Administration
                  •      Administer IWILFIN orally twice daily, with or without food, for two years or until recurrence of
                         disease or unacceptable toxicity [see Clinical Pharmacology (12.3)].
                  •      IWILFIN tablets can be swallowed whole, chewed, or crushed.
           Crushed Preparation
                  •      For patients who have difficulty swallowing tablets, IWILFIN can be chewed, or crushed then mixed
                         with two tablespoons of soft food or liquid.
                  •      Visually confirm the entire contents are consumed. If any crushed tablet particles remain in the
                         container, mix with an additional small volume (e.g., no more than one ounce, 30 mL) of soft food or
                         liquid.
                  •      Discard crushed tablet preparation after one hour.



Reference ID: 5293147
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         Missed Dose
               •     A missed dose of IWILFIN should be administered as soon as possible. If the next dose is due within 7
                     hours, the missed dose should be skipped.
               •     If vomiting occurs after taking IWILFIN, an additional dose should not be administered. Continue with
                     the next scheduled dose.
         3                 DOSAGE FORMS AND STRENGTHS
         Tablets: 192 mg eflornithine, white to off-white, round, imprinted with “EFL” on one side and “192” on the
         other side.
         4                 CONTRAINDICATIONS
         None.
         5                 WARNINGS AND PRECAUTIONS
         5.1               Myelosuppression
         IWILFIN can cause myelosuppression. In the pooled safety population [see Adverse Reactions (6.1)], Grade 3
         or 4 neutropenia occurred in 4.2% of patients. Febrile neutropenia occurred in 0.6% of patients. Bone marrow
         failure occurred in 1 patient. Grade 3 or 4 thrombocytopenia occurred in 1.4% of patients. Grade 3 anemia
         occurred in 3.3% of patients.
         Perform blood counts including neutrophil count, platelet count, and hemoglobin level prior to administration of
         IWILFIN and periodically during treatment. Withhold, reduce the dose, or permanently discontinue IWILFIN
         based on severity [see Dosage and Administration (2.3)].
         5.2              Hepatotoxicity
         IWILFIN can cause hepatotoxicity. In the pooled safety population [see Adverse Reactions (6.1)], Grade 3 or 4
         events of increased alanine aminotransferase (ALT) occurred in 11% of patients. Grade 3 or 4 events of
         increased aspartate aminotransferase (AST) occurred in 6% of patients. Grade 3 or 4 events of increased
         bilirubin occurred in 0.3% of patients. Increased ALT/AST leading to dose interruption or reduction occurred in
         2.5% of patients. IWILFIN was discontinued due to increased ALT/AST in 0.6% of patients.
         Perform liver function tests (ALT, AST, and total bilirubin) prior to the start of IWILFIN, every month for the
         first six months of treatment, then once every 3 months or as clinically indicated, with more frequent testing in
         patients who develop transaminase or bilirubin elevations. Withhold and reduce the dose or permanently
         discontinue IWILFIN based on severity [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
         5.3               Hearing Loss
         IWILFIN can cause hearing loss. In the pooled safety population [see Adverse Reactions (6.1)], 81% of patients
         had an abnormal audiogram at baseline. New or worsening hearing loss occurred in 13% of patients who
         received IWILFIN; hearing loss worsened from baseline to Grade 3 or 4 in 12% of patients. Tinnitus occurred
         in 1 patient. Hearing loss leading to dose interruption or reduction occurred in 4% of patients. New or


Reference ID: 5293147
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         worsening hearing loss requiring new use of hearing aids occurred in 7% of patients. IWILFIN was
         discontinued due to hearing loss in 1.4% of patients. Among all patients with new or worsening hearing loss
         during IWILFIN treatment, the hearing loss resolved to baseline in 9% of patients. Among 18 patients who
         experienced new or worsening hearing loss and had dose modifications, 67% (N=12) improved or resolved to
        baseline.
        Perform audiogram prior to initiation of therapy and at 6 month intervals, or as clinically indicated, to monitor
        for potential hearing loss. Withhold and reduce the dose or permanently discontinue IWILFIN based on severity
        [see Dosage and Administration (2.1, 2.3)].
         5.4              Embryo-Fetal Toxicity
         Based on findings from animal studies and its mechanism of action, IWILFIN can cause fetal harm when
         administered to a pregnant woman. In animal reproduction studies, oral administration of eflornithine to
         pregnant rats and rabbits during the period of organogenesis resulted in embryolethality at doses equivalent to
         the recommended human dose.
         Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of
         reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the
         last dose. Advise males with female partners of reproductive potential to use effective contraception during
         treatment with IWILFIN and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].
         6                 ADVERSE REACTIONS
         The following clinically significant adverse reactions are described elsewhere in the labeling:
                     •     Myelosuppression [see Warnings and Precautions (5.1)]
                     •     Hepatotoxicity [see Warnings and Precautions (5.2)]
                     •     Hearing Loss [see Warnings and Precautions (5.3)]
         6.1              Clinical Trials Experience
         Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
         clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
         reflect rates observed in clinical practice.
         The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to
         IWILFIN as a single agent, taken orally at doses ranging from 192 - 768 mg twice daily, based on body surface
         area (BSA), until disease progression, unacceptable toxicity, or for a maximum of 2 years in patients who
         demonstrated at least a partial response to prior multiagent, multimodality therapy for newly diagnosed or
        relapsed/refractory high-risk neuroblastoma in Study 3b (n=101; NCT02395666) and Study 14 (n=259;
        NCT02679144). Among 360 patients who received IWILFIN, 84% were exposed for 6 months or longer and
        73% were exposed for greater than one year.                               In this pooled safety population, the most common (≥5%) adverse
        reactions were hearing loss (11%), otitis media (10%), pyrexia (7%), pneumonia (5%), and diarrhea (5%). The
        most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT (11%), increased AST (6%),
        decreased neutrophils (4.2%), and decreased hemoglobin (3.3%).
        Study 3b


Reference ID: 5293147
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             The safety of IWILFIN was evaluated in Study 3b [see Clinical Studies (14.1)]. Eligible patients were pediatric
             patients with high-risk neuroblastoma (HRNB) who demonstrated at least a partial response to prior multiagent,
             multimodality therapy including induction, consolidation, and anti-GD2 immunotherapy. Patients received
             IWILFIN as a single agent taken orally at doses ranging from 192 - 768 mg twice daily, based on body surface
             area (BSA), until disease progression, unacceptable toxicity, or for a maximum of 2 years (N=85). Among
             patients who received IWILFIN, 93% were exposed for 6 months or longer and 89% were exposed for greater
             than one year.
             The median age of patients who received IWILFIN was 4 years (range: 1 to 17); 59% male; 85% White, 7%
             Black, 1% Asian, 8% Hispanic or Latino; 87% had International Neuroblastoma Staging System Stage 4
             disease; 47% had neuroblastoma with known MYCN-amplification.
             Serious adverse reactions occurred in 12% of patients who received IWILFIN. Serious adverse reactions in >1
             patient included skin infection (3 patients).
             Permanent discontinuation of IWILFIN due to an adverse reaction occurred in 11% of patients. Adverse
             reactions which resulted in permanent discontinuation of IWILFIN in >1 patient included hearing loss.
             Dose reductions of IWILFIN due to an adverse reaction occurred in 8% of patients. Adverse reactions which
             required dose reductions in >1 patient included hearing loss.
             The most common (≥5%) adverse reactions, including laboratory abnormalities, were otitis media, diarrhea,
             cough, sinusitis, pneumonia, upper respiratory tract infection, conjunctivitis, vomiting, pyrexia, allergic rhinitis,
             decreased neutrophils, increased ALT, increased AST, hearing loss, skin infection, and urinary tract infection.
             Table 4 summarizes the adverse reactions in Study 3b.
             Table 4:                            Adverse Reactions (≥5%) in Patients with HRNB Who Received IWILFIN in Study 3b
               Adverse Reactiona                                                                                                                 IWILFIN
                                                                                                                                                     (n=85)
                                                                                                                               All Gradesb,c                 Grade 3
                                                                                                                                           (%)                     (%)
               Infections
               Otitis media                                                                                                                 32                      2.4
               Sinusitis                                                                                                                    13                        0
               Pneumonia                                                                                                                    12                      1.2
               Upper respiratory tract infection                                                                                            11                        0
               Conjunctivitis                                                                                                               11                        0
               Skin infection                                                                                                                 7                     4.7
               Urinary tract infection                                                                                                        6                     1.2
               Gastrointestinal Disorders
               Diarrhead                                                                                                                    15                      3.5
               Vomiting                                                                                                                     11                      1.2


Reference ID: 5293147
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               Adverse Reactiona                                                                                                                                 IWILFIN
                                                                                                                                                                     (n=85)
                                                                                                                               All Gradesb,c                                                 Grade 3
                                                                                                                                           (%)                                                     (%)
               Respiratory Disorders
               Cough                                                                                                                        15                                                        0
               Allergic rhinitis                                                                                                            11                                                        0
               General Disorders
               Pyrexia                                                                                                                      11                                                      1.2
               Ear and Labyrinth Disorders
               Hearing loss                                                                                                                   7                                                       7
             a Severity as defined by CTCAE Version 4.03.
             b Grade 1 adverse events were not comprehensively collected in Study 3b.
             c No Grade 4 or 5 events were reported.
             d Includes colitis.
             Clinically relevant adverse reactions in <5% of patients who received IWILFIN included rash, extremity pain,
             and alopecia.
             Table 5 summarizes the laboratory abnormalities in Study 3b.
             Table 5:                            Select Laboratory Abnormalities (≥1%) in Patients with HRNB Who Received IWILFIN in
                                                 Study 3b
               Laboratory Abnormalitya                                                                                                                               IWILFIN
                                                                                                                                                                          (n=85)
                                                                                                                                               All Gradesb,c                      Grade 3 or 4
                                                                                                                                                           (%)                                (%)
               Chemistry
               Increased ALT                                                                                                                                  9                                 7d
               Increased AST                                                                                                                                  8                                 6d
               Increased alkaline phosphatase                                                                                                               4.7                              2.4d
               Decreased potassium                                                                                                                          2.4                              2.4d
               Decreased glucose                                                                                                                            2.4                               1.1
               Decreased sodium                                                                                                                             2.4                              2.4d
               Increased potassium                                                                                                                          1.2                                  0
               Increased glucose                                                                                                                            1.2                                  0
               Hematology
               Decreased neutrophils                                                                                                                          9                                  8


Reference ID: 5293147
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              Decreased hemoglobin                                                                                            4.7  2.4d
              Decreased white blood cells                                                                                     2.4     0
              Decreased platelets                                                                                             1.2     0
            a Severity as defined by CTCAE Version 4.03.
            b Grade 1 adverse events were not comprehensively collected in Study 3b.
            cNo Grade 5 events were reported.
            d No Grade 4 occurred.
            8                       USE IN SPECIFIC POPULATIONS
           8.1                     Pregnancy
            Risk Summary
            Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)],
            IWILFIN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral
            administration of eflornithine to pregnant rats and rabbits during the period of organogenesis resulted in
            embryolethality at doses equivalent to the recommended human dose [see Data]. There are no available data on
            the use of IWILFIN in pregnant women. Advise pregnant women and females of reproductive potential of the
            potential risk to a fetus.
            In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
            clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
            Data
            Animal Data
            In an embryo-fetal development study, once daily oral administration of 30, 80 or 200 mg/kg/day eflornithine to
            pregnant rats during the period of organogenesis (gestation day 6 to 7) resulted in reduced fetal body weights
            and an increase in the incidence of skeletal variations (presence of a 14th rudimentary rib, 14th full rib, 27th
            presacral vertebrae) at 200 mg/kg/day [approximately 0.8 to 2 times the recommended human dose of 1152 ±
            384 mg/m2/day based on body surface area (BSA)]. In a dose range-finding embryo-fetal development study,
           pregnant rats receiving oral administration of up to 2000 mg/kg/day eflornithine during the period of
           organogenesis exhibited increased early resorptions and post-implantation loss beginning at 300 mg/kg/day
           (approximately 1 to 2 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA), with
            100% post-implantation loss and no viable fetuses at ≥800 mg/kg/day (approximately ≥3 to 6  times the
            recommended human dose of 1152 ± 384 mg/m2/day based on BSA).
            In an embryo-fetal development study in rabbits, once daily oral administration of 15, 45 or 135 mg/kg/day
            eflornithine to pregnant animals during the period of organogenesis (gestation day 7 to 20) resulted in reduced
            gravid uterine weight accompanied by increased pre-implantation and post-implantation loss, increased early
            resorptions, and reduced fetal body weights at 135 mg/kg/day (approximately 1 to 2 times the recommended
            human dose of 1152 ± 384 mg/m2/day based on BSA). Eflornithine resulted in abortions in one animal at 15
            mg/kg/day (approximately 0.1 to 0.2 times the recommended human dose of 1152 ± 384 mg/m2/day based on
            BSA) and one animal at 135 mg/kg/day. In a dose range-finding embryo-fetal development study, pregnant
           rabbits receiving oral administration of up to 500 mg/kg/day eflornithine during the period of organogenesis
           exhibited 100% post-implantation loss and no viable fetuses at 500 mg/kg/day (approximately 4 to 8 times the


Reference ID: 5293147
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         recommended human dose of 1152 ± 384 mg/m2/day based on BSA). There was no clear evidence of
         eflornithine-related fetal malformations in rats or rabbits.
         8.2               Lactation
         Risk Summary
         There are no data on the presence of eflornithine in human milk, the effects on the breastfed child, or on milk
         production. Because of the potential for serious adverse reactions in breastfed children, advise women not to
         breastfeed during treatment with IWILFIN and for 1 week after the last dose.
         8.3               Females and Males of Reproductive Potential
         Based on animal data and its mechanism of action, IWILFIN can cause fetal harm when administered to a
         pregnant woman [see Use in Specific Populations (8.1)].
         Pregnancy Testing
         Verify pregnancy status in females of reproductive potential prior to initiating IWILFIN [see Use in Specific
         Populations (8.1)].
         Contraception
         Females
         Advise females of reproductive potential to use effective contraception during treatment with IWILFIN and for
         1 week after the last dose.
         Males
         Advise males with female partners of reproductive potential to use effective contraception during treatment with
         IWILFIN and for 1 week after the last dose.
         8.4               Pediatric Use
         The safety and effectiveness of IWILFIN have been established to reduce the risk of relapse in pediatric patients
         with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent,
         multimodality therapy including anti-GD2 immunotherapy. Use of IWILFIN for this indication is supported by
         evidence from adequate and well-controlled studies in pediatric patients with a median age of 4 years (range: 1
         to 17) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].
         The safety and effectiveness of IWILFIN have not been established in pediatric patients for other indications
         [see Indications and Usage (1)].
         11                DESCRIPTION
         IWILFIN is an ornithine decarboxylase inhibitor. The chemical name of eflornithine hydrochloride is 2,5­
         diamino-2-(difluoromethyl) pentanoic acid hydrochloride hydrate with a molecular formula of
         C6H12F2N2O2•HCl•H2O. Its molecular weight is 236.65g/mol for the salt and hydrate form and 182.17 g/mol for
         the anhydrous free base form. Eflornithine hydrochloride is a white to off-white powder, freely soluble in water
         and sparingly soluble in ethanol. The chemical structure of eflornithine hydrochloride is:


Reference ID: 5293147
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          HzN-                  HzN              OH
                            HCI                HzO
         IWILFIN is available as a round, white to off-white tablet for oral administration. Each tablet contains 192 mg
         eflornithine, equivalent to 250 mg of eflornithine hydrochloride, and the following inactive ingredients: 220 mg
        silicified microcrystalline cellulose, 25 mg partially pregelatinized maize starch, 2.5 mg colloidal silicon
        dioxide, and 2.5 mg vegetable source magnesium stearate.
         12                CLINICAL PHARMACOLOGY
         12.1              Mechanism of Action
         Eflornithine is an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), the first and rate-limiting
         enzyme in the biosynthesis of polyamines and a transcriptional target of MYCN. Polyamines are involved in
         differentiation and proliferation of mammalian cells and are important for neoplastic transformation. Inhibition
         of polyamine synthesis by eflornithine restored the balance of the LIN28/Let-7 metabolic pathway, which is
         involved in regulation of cancer stem cells and glycolytic metabolism, by decreasing expression of the
         oncogenic drivers MYCN and LIN28B in MYCN-amplified neuroblastoma. In vitro, eflornithine induced
         senescence and suppressed neurosphere formation in MYCN-amplified and MYCN non-amplified neuroblastoma
         cells, indicating a cytostatic effect. Treatment with eflornithine prevented or delayed tumor formation in mice
        injected with limiting dilutions of MYCN-amplified neuroblastoma cells.
         12.2              Pharmacodynamics
         Eflornithine exposure-response relationships and the time course of pharmacodynamic responses are unknown.

         Cardiac Electrophysiology
         At the recommended dose, IWILFIN did not result in a large mean increase (i.e., >20 ms) of the QTc interval.

         12.3              Pharmacokinetics
         Absorption
         Following oral administrations of IWILFIN, peak plasma concentrations of eflornithine (Cmax) were achieved
         (Tmax) 3.5 hours post dosing.
        Effect of Food
        The Cmax and AUC (area under the concentration-time curve) of eflornithine were not affected by food (high fat
         and high calories). Administration of crushed tablets in a standard pudding admixture had no effect on
         eflornithine exposure (Cmax and AUC6h).


Reference ID: 5293147
---
          Distribution
          Eflornithine does not specifically bind to human plasma proteins. Eflornithine volume of distribution (Vz/F) is
          24.3 L.
          Elimination
          Excretion
          Terminal plasma elimination half-life of eflornithine is 3.5 hours. Clearance (CL/F) is 5.3 L/h.
          Specific Populations
          Pharmacokinetic analyses from patients in Study 14 suggested that age (1 year to 19 years), sex, or body surface
          area (0.4 m2 to 2 m2), and mild hepatic impairment (bilirubin ≤ULN and AST>ULN or bilirubin >1 x ULN and
          any AST) had no clinically meaningful effects on eflornithine exposure.
          Renal Impairment
          No studies have been conducted in patients with renal impairment.
          13                    NONCLINICAL TOXICOLOGY
          13.1                  Carcinogenesis, Mutagenesis, Impairment of Fertility
          In a 2-year carcinogenicity study, once daily oral administration of eflornithine to female rats did not result in
          drug-related neoplasms at doses up to 600 mg/kg/day (10.5 times the human Cmax at the recommended clinical
          dose of 1152 ± 384 mg/m2).
          Eflornithine was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay.
          Dedicated fertility studies were not conducted with eflornithine.
          14                    CLINICAL STUDIES
          The efficacy of IWILFIN is based on an externally controlled trial comparison of Study 3b (investigational arm)
          and Study ANBL0032 (clinical trial-derived external control arm).
          Study 3b
          Study 3b (NCT02395666) was a multi-center, open label, non-randomized trial with two cohorts. Eligible
          patients in one cohort (Stratum 1) were pediatric patients with high-risk neuroblastoma (HRNB) who
          demonstrated at least a partial response to prior multiagent, multimodality therapy, including induction,
          consolidation, and anti-GD2 immunotherapy. A total of 105 eligible patients received IWILFIN orally twice
          daily, dosage based on body surface area (BSA) until disease progression, unacceptable toxicity, or for a
          maximum of 2 years [see Dosage and Administration (2.1)]. Tumor assessments were performed at 3, 6, 9, 12,
          18 months, completion of treatment, and as clinically indicated. Following completion of IWILFIN therapy,
          patients were followed for a total duration of 7 years. The major efficacy outcome measure was event free
          survival (EFS), defined as disease progression, relapse, secondary cancer, or death due to any cause. An
          additional efficacy outcome measure was overall survival (OS), defined as death due to any cause. Study 3b
          was prospectively designed to compare outcomes to the historical EFS rate from Study ANBL0032 reported in
          published literature.
          External Comparator: ANBL0032


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         The external control arm was derived from 1,241 patients on the experimental arm of Study ANBL0032, a
         multi-center, open-label, randomized trial of dinutuximab, granulocyte-macrophage colony-stimulating factor,
         interleukin-2, and cis-retinoic acid compared to cis-retinoic acid alone in pediatric patients with HRNB
         previously treated with induction and consolidation therapy who demonstrated at least a partial response. Tumor
        assessments were performed post-immunotherapy at 3, 6, 9, 12, 18, 24, 30, and 36 months, then per standard of
        care for a total of 10 years.
        Externally Controlled Trial
        The efficacy population for the comparative analysis of Study 3b and ANBL0032 included patients from both
        studies who were less than 21 years of age with histologic verification of HRNB and who demonstrated at least
        a partial response based on imaging, with no evidence of disease in the bone marrow, at the end of
        immunotherapy, and did not experience an EFS event prior to starting IWILFIN maintenance therapy (for Study
        3b), or for at least 30 days from the end of immunotherapy (for ANBL0032). Eligible patients on Study 3b
        received immunotherapy on ANBL0032 or were treated off study according to the ANBL0032 protocol.
        Patients who met the criteria for the comparison and had complete data for specified clinical covariates were
        matched (1:3) using propensity scores; the matched efficacy populations for the primary analysis included 90
        patients treated with IWILFIN and 270 control patients from ANBL0032. The demographic characteristics of
        the primary analysis population (N=360) were 59% male; median age at diagnosis 3 years (range: 0.1 to 20.1);
        88% White, 6% Black, 4% Asian, 7% Hispanic. The majority of patients had Stage 4 disease (86%) and MYCN
        amplification was observed in 44% of tumors. End of immunotherapy responses were complete response (CR;
        87%), very good partial response (VGPR; 8%), or partial response (PR; 5%).
        In the protocol-specified primary analysis, the EFS hazard ratio (HR) was 0.48 (95% CI: 0.27, 0.85) and OS HR
        was 0.32 (95% CI: 0.15, 0.70). The Kaplan-Meier plot for the primary analysis of EFS, with shaded bands for
        each curve representing the point-wise 95% confidence intervals, is shown in Figure 1. Given the uncertainty in
        treatment effect estimation associated with the externally controlled study design, supplementary analyses in
        subpopulations or using alternative statistical methods were performed. In these analyses, the EFS HR ranged
        from 0.43 (95% CI: 0.23, 0.79) to 0.59 (95% CI: 0.28, 1.27), and the OS HR ranged from 0.29 (95% CI: 0.11,
        0.72) to 0.45 (95% CI: 0.21, 0.98).













Reference ID: 5293147
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                       Figure 1: Kaplan-Meier Curve for Event Free Survival for Protocol-Specified Primary Analysis in the
                       Externally Controlled Trial

                                                  1.0
                                                  0.9
                                1 QI              0.8
                                 -nl
                                0:::
                                ] nl              0.7
                                  >
                                ·s;               0.6
                                  ...
                                  ::::s
                              2 V,QI              0.5
                                  QI
                                u....
                                1 C:              04
                                 -QI              0.3
                                w >
                                                  0.2
                                                  0.1                                                 IWILFI
                                                                                                       IWIL           FIN
                                                                                                       Conttol
                                                                                                       Control
                                                  0.0
                                                                0                                                  2                   3     4                         5                     6                      7       8     9     10     11     12
                            At nisk                                                                                                              Time From End of Immunotherapy (Years
                            At risk                                                                                                              Time                From               End       of lmmunotherapy (Years)
                            WILFIN
                             IWILFIN                            90                        83                        78                   77   76                        70                    47                     27        2     0
                            Contiol
                             Control                           270                       229                       211                 200   164                       117                    80                     49      29    15       9      3      0
                       16                                               HOW SUPPLIED/STORAGE AND HANDLING
                       IWILFIN (eflornithine) is available as 192 mg round, white to off-white tablets imprinted with EFL on one side
                       and 192 on the other side; approximately 11 mm in diameter and supplied as follows:
                                                        •               Bottle of 100 tablets containing desiccant, NDC 78670-150-01
                       Store at room temperature, 20oC to 25°C (68oF to77°F), excursions permitted between 15°C to 30°C (59°F to
                       86°F) [see USP Controlled Room Temperature].
                       17                                               PATIENT COUNSELING INFORMATION
                       Advise the patient to read the FDA-approved patient labeling (Patient Information).
                       Myelosuppression
                       Inform patients and caregivers of the risk of bone marrow suppression and to promptly report any signs or
                       symptoms of thrombocytopenia, anemia, or infection [see Warnings and Precautions (5.1)].
                       Hepatotoxicity
                       Inform patients and caregivers of the risk of hepatotoxicity and to promptly report any signs or symptoms of
                       hepatotoxicity [see Warnings and Precautions (5.2)].
                       Hearing Loss


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         Inform patients and caregivers of the risk of hearing loss, and to promptly report any signs or symptoms of new
         or worsening hearing loss [see Warnings and Precautions (5.3)].
         Embryofetal Toxicity
         Inform patients and caregivers that IWILFIN can be harmful to a developing fetus and cause loss of pregnancy
         [see Warnings and Precautions (5.4)]. Advise females of reproductive potential to use effective contraception
         during treatment with IWILFIN and for 1 week after the last dose. Advise males with female partners of
         reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the
         last dose [see Use in Specific Populations (8.3)].
        Lactation
        Advise women not to breastfeed during treatment with IWILFIN and for 1 week after the last dose [see Use in
        Specific Populations (8.2)].
        US W 6ri2JMeds·      IOr            MA
         Distributed by:
         USWM, LLC
         4441 Springdale Road
         Louisville, KY 40241
         ©2023. IWILFIN™ is a trademark of USWM, LLC.
         FPI-0026


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                                                                                            Patient Information
                                                                                          IWILFINTM (I-WILL-fin)
                                                                                                 (eflornithine)
                                                                                                       tablets
          What is IWILFIN?
          IWILFIN is a prescription medicine used to reduce the risk of relapse in adults and children with high-risk neuroblastoma
          (HRNB) who have had at least a partial response to certain prior therapies.
          Before you take IWILFIN, tell your healthcare provider about all of your medical conditions, including if you:
          •    have hearing problems
          •    are pregnant or plan to become pregnant. IWILFIN can harm your unborn baby. Tell your healthcare provider right
               away if you become pregnant during treatment with IWILFIN or think you may be pregnant.
               o     Females who are able to become pregnant should have a pregnancy test before starting treatment with IWILFIN.
                     You should use effective birth control during treatment with IWILFIN and for 1 week after the last dose.
               o     Males who have female partners who are able to become pregnant should use effective birth control during
                     treatment with IWILFIN and for 1 week after the last dose.
          •    are breastfeeding or plan to breastfeed. It is not known if IWILFIN passes into your breast milk. Do not breastfeed
               during treatment with IWILFIN and for 1 week after the last dose.
          Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
          vitamins, and herbal supplements.
          How should I take IWILFIN?
          •    Take IWILFIN exactly as your healthcare provider tells you to take it.
          •    Take IWILFIN 2 times a day with or without food.
          •    Swallow tablets whole. If you cannot swallow tablets whole, IWILFIN can be chewed, or crushed then mixed with soft
               food or liquid. If you are crushing IWILFIN tablets:
               o     IWILFIN can be crushed then mixed with 2 tablespoons of soft food or liquid.
               o     Eat the entire mixture.
               o     If any crushed tablet pieces remain, mix with another small amount (about 2 tablespoons) of soft food or liquid.
               o     Take all of the mixture within 1 hour of mixing. Throw away any mixture left after 1 hour.
          •    If you miss a dose of IWILFIN, take it as soon as you remember. If it is within 7 hours of your next scheduled dose, skip
               the missed dose and take your next dose at your regular time.
          •    If you vomit after taking a dose, do not take an extra dose. Take your next dose at your regular time.
          What are the possible side effects of IWILFIN?
          IWILFIN may cause serious side effects, including:
          •    Low blood cell counts. IWILFIN can cause low blood cell counts and failure of your bone marrow to make enough
               platelets, red blood cells, or white blood cells. Your healthcare provider will monitor your blood cell counts before
               starting and during treatment with IWILFIN. Tell your healthcare provider right away if you develop symptoms of low
               blood cell counts, including:
               o     fever (temperature 100.4°F or higher)                                                            o      feeling unusually tired or weak
               o     easy bruising or bleeding                                                                        o      shortness of breath
               o     blood in your urine or stools                                                                    o      chills or shivering
          •    Liver problems. Your healthcare provider will do blood tests before starting, every month for the first 6 months, and
               regularly during treatment with IWILFIN to check your liver. Tell your healthcare provider if you develop symptoms of
               liver problems, including:
               o     your skin or the white part of your eyes turns yellow                                             o      nausea or vomiting
                     (jaundice)                                                                                        o      easy bruising or bleeding
               o     dark or “tea-colored” urine                                                                       o      loss of appetite
               o     light-colored stools (bowel movements)                                                            o      pain, aching, or tenderness on the right side of
                                                                                                                              your stomach-area (abdomen)
          •    New or worsening hearing loss. Hearing loss is common during treatment with IWILFIN and can also be serious.
               Your healthcare provider will check your hearing before you start and during treatment with IWILFIN. Some people
               have needed to use hearing aids. Tell your healthcare provider right way if you get ringing in your ears or any new or
               worsening hearing loss.

          The most common side effects of IWILFIN include:
          •   ear infection                                                  •      red and swollen eyes (pink eye)
          •   diarrhea                                                       •      vomiting
          •   cough                                                          •      stuffy, runny, itchy nose or sneezing (allergic rhinitis)
          •   sinus infection                                                •      fever
          •   pneumonia                                                      •      skin infection
          •   upper respiratory tract infection                              •      urinary tract infection
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              These are not all the possible side effects of IWILFIN.
              Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
              How should I store IWILFIN?
              •       Store IWILFIN at room temperature between 68°F to 77°F (20°C to 25°C).
              Keep IWILFIN and all medicines out of the reach of children.
              General information about the safe and effective use of IWILFIN:
              Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use
              IWILFIN for a condition for which it was not prescribed. Do not give IWILFIN to other people, even if they have the same
              symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about
              IWILFIN that is written for health professionals.
              What are the ingredients in IWILFIN?
              Active ingredient: eflornithine
              Inactive ingredients: silicified microcrystalline cellulose, partially pregelatinized maize starch, colloidal silicon dioxide,
              and vegetable source magnesium stearate.

              Distributed by:
              USWM, LLC 4441 Springdale Road Louisville, KY 40241
              ©2023. IWILFIN™ is a trademark of USWM, LLC.

              For more information, go to www.IWILFIN.com or call 1-877-IWILFIN.
              This Patient Information has been approved by the U.S. Food and Drug Administration                                             Issued: 12/2023
Reference ID: 5293147